The goal of this project is to optimize the use of "suicidal lymphocytes" as a means of controlling graft-versus-host disease (GVHD) thereby expanding the population of patients able to benefit from the graft-vs.-leukemia effect (GVL) associated with allogeneic transplantation. The ability to fully harness the immunologically mediated graft-versus-leukemia (GVL) effect noted after allogeneic marrow or stem cell transplantation is limited by the development of GVHD. Current therapies, designed to prevent or treat GVHD are sub optimal and the risk of GVHD remains a major barrier preventing many leukemia patients from undergoing allogeneic transplantation and benefiting from a GVL effect. A novel strategy to control GVHD is to selectively eliminate the GVHD initiating T-cell after infusion, instead of suppressing the function of all T-cells. This selectivity is generated by transducing T-cells ex-vivo with a retrovirus containing the herpes simplex virus-thymidine kinase (HSV-TK) gene. These "suicidal" lymphocytes are then infused into patient. Should GVHD develop the "suicidal lymphocytes" are eliminated by the administration of ganciclovir (GCV) to which they are now sensitive. Several small clinical trials have demonstrated proof of principle but have also highlighted technical problems. During the prior funding cycle of NIH P01 grant CA 49639 ("the Therapy of CML") we developed a murine model using retrovirally transduced murine T-cells to help optimize the use of "suicidal" lymphocytes. The proposed studies will continue to determine the efficacy of these transduced lymphocytes in established murine models and investigate means of optimizing and expanding their use to enable more patients to benefit from the GVL effect. Specific Aim 1. Demonstrate that LNGFR-TK-infected lymphocytes are capable of generating a GVL effect in the MHC matched allogeneic transplant setting against the AKR/J derived M1 T-cell leukemia, or against a retrovirally transduced Bcr-abl based "CML like" myeloproliferative disorder. Specific Aim 2. Adapt the model to test if GVHD can still be controlled when suicidal lymphocyte are used in the non-myeloablative and haploidentical allogeneic transplant settings. Specific Aim 3. Attempt to increased the anti-leukemic specificity and the GVL effect by using leukemia derived dendritic cells to stimulate and prime the T-cells during the generation of TK+ lymphocytes. Specific Aim 4: Test whether DLI using suicidal lymphocytes can be utilized as therapy against minimal residual disease during remission without marrow or stem cell support.